1. Technical Field
This invention relates generally to a method for promoting the regeneration of composite tissues, and is particularly related to the use of the GM284 in such a method.
2. Related Art
Injured tissues are able to heal by regeneration, by repair, or by a combination of these processes. Regeneration results in the re-establishment of the original tissue structure and function. In contrast, tissue repair results in the replacement of the original tissue with a patch of connective tissue, or scar, which is functionally inferior to the original tissue. The response of most mammalian tissues to injury falls within a spectrum bounded by regeneration and repair.
In mammals and other higher organisms there is a failure of regeneration of composite or complex tissues. Bodily structures comprised of composite tissues, such as a limb or digit, or an appendage, such as an ear or nose, are made of numerous cell types arranged in an organized and iterative structure that is preserved from individual to individual. When composite tissues or bodily structures comprised of composite tissues are injured, regeneration requires the coordinated growth, and interactions of numerous cell types within the composite tissues to regenerate a bodily structure that effectively indistinguishable from the original.
The regeneration of composite tissues and entire body parts are biological capabilities shared by many lower species. For example, die starfish can regenerate entire limbs after amputations and the snail can regenerate its head. In contrast, most vertebrates have no ability to regenerate entire body parts. It is not clear if the inability of vertebrate composite tissues to regenerate represents a true inability to re-form these tissues following injury, or if the molecular and cellular mechanisms that control the processes have been re-directed for use in, other biological processes. The discovery presented herein by the inventor argues for the latter.
The MRL mouse is a spontaneously occurring mutant strain that differs from most mammals in that it regenerates composite tissue following injury. When a hole is placed through the ear of a wild-type mouse, there is little or no regeneration. In contrast, the placement of a full thickness hole through the ear of the MRL mouse results in complete regeneration of all the cell-types within the ear and the closure of the hole within 30 days (Heber-Katz, E., The regenerating mouse ear, Semin Cell Dev Biol 10, 415-9 (1999); Clark, L. D., Clark, R. K, & Heber-Katz, E., A new murine model for mammalian wound repair and regeneration, Clin Immunol Immunopathol 88, 35-45 (1998); Heber-Katz, E., Leferovich, J. M., Bedelbaeva, K. & Gourevitch, D. Spallanzani's mouse: a model of restoration and regeneration. Curr Top Microbiol Immunol 280, 165-89 (2004)).
Analysis of the genetic loci that are involved in this unique biology has demonstrated a complex set of traits that have been associated with 11 quantitative trait loci (Heber-Katz, E., et al. Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. Castaneus mice, Wound Repair Regen 12, 384-92 (2004)).
The regenerative capacity of the MRL mouse is not restricted to the ear, Cryoinfarction of the MRL mouse heart results in the anatomic and functional recovery of the heart, whereas there is no such regeneration in the wild-type heart in any mammalian species.
The inventor has previously shown that GM284, a non-immunosuppressive immunophilin ligand, promotes accelerated and extensive regeneration of skin following full-thickness lesions (U.S. patent application Ser. No. 10/290,657; Publication No. 20040092440) and of peripheral nerves following mechanical transection (U.S. patent application Ser. No. 10/290,654; Publication No. 20040026681).
The inventor tested the ability of GM284 to promote the regeneration of the composite tissues of the murine ear. The inventor has concluded from his experiments that GM284 activates a cascade of interactions that lock tissues in a state of regeneration. Moreover, the inventor's unexpected discovery suggests that these events are conserved across evolutionary lines, and that GM284 takes advantage of their existence in mammals.